A series of 22 Substance P analogs, characterized by elongation or shortening of the peptide chain or by replacement of some amino acids, will be synthesized and pharmacologically analyzed in order to elucidate the chemical and biological reactivity of Substance P, and to support and expedite the establishment of the clinical benefits of Substance P in treating disease. The availability of analogs will open up the possibility to study the agonist-antagonist interaction in more detail, and to determine which part of the molecule is important for affinity and activity, respectively, for Substance P. Of the eight different amino acids in the undecapeptide sequence of Substance P, Arg1-, Lys3-, Phe7-, and Phe8- appear to be the four crucial amino acids. The Arg1- and Lys3- moieties, in protonated form, could be very important for activity and potency because they contribute an ionic nature to the molecule. The Phe7-Phe8-moiety could contribute unique structural specificity to the entire molecule because of possible pi-pi bond interaction with a receptor site. Modification of these amino acids by elimination or substitution, as well as modification of both termini of the peptide chain by substitution, elimination, or elongation, will allow us to design Substance P analogs in order to (1) study the immunochemical affinity and reactivity of Substance P, (2) act as an inhibitor of Substance P, and/or (3) prolong the activity of Substance P to make it more clinically effective. The analogs will be synthesized by the solid phase technique on a Beckman 990 automatic peptide synthesizer, purified, and appropriately characterized by thin layer chromatography, amino acid analyses, electrophoresis, and optical rotation. The pharmacological studies will be carried out by Dr. Bengt Pernow of the Clinical Physiology Department of the Karolinska Institute, Stockholm, Sweden, through a continuing cooperative agreement with Dr. Folkers.